共查询到20条相似文献,搜索用时 31 毫秒
1.
Shimmyo Y Kihara T Akaike A Niidome T Sugimoto H 《Biochimica et biophysica acta》2008,1780(5):819-825
Generation and accumulation of the amyloid beta peptide (Abeta) following proteolytic processing of the amyloid precursor protein (APP) by BACE-1 (Beta-site APP Cleaving Enzyme-1, beta-secretase) and gamma-secretase is a main causal factor of Alzheimer's disease (AD). Consequently, inhibition of BACE-1, a rate-limiting enzyme in the production of Abeta, is an attractive therapeutic approach for the treatment of AD. In this study, we discovered that natural flavonoids act as non-peptidic BACE-1 inhibitors and potently inhibit BACE-1 activity and reduce the level of secreted Abeta in primary cortical neurons. In addition, we demonstrated the calculated docking poses of flavonoids to BACE-1 and revealed the interactions of flavonoids with the BACE-1 catalytic center. We firstly revealed novel pharmacophore features of flavonoids by using cell-free, cell-based and in silico docking studies. These results contribute to the development of new BACE-1 inhibitors for the treatment of AD. 相似文献
2.
Yoshiari Shimmyo Takeshi Kihara Akinori Akaike Tetsuhiro Niidome Hachiro Sugimoto 《Biochimica et Biophysica Acta (BBA)/General Subjects》2008
Generation and accumulation of the amyloid β peptide (Aβ) following proteolytic processing of the amyloid precursor protein (APP) by BACE-1 (Beta-site APP Cleaving Enzyme-1, β-secretase) and γ-secretase is a main causal factor of Alzheimer's disease (AD). Consequently, inhibition of BACE-1, a rate-limiting enzyme in the production of Aβ, is an attractive therapeutic approach for the treatment of AD. In this study, we discovered that natural flavonoids act as non-peptidic BACE-1 inhibitors and potently inhibit BACE-1 activity and reduce the level of secreted Aβ in primary cortical neurons. In addition, we demonstrated the calculated docking poses of flavonoids to BACE-1 and revealed the interactions of flavonoids with the BACE-1 catalytic center. We firstly revealed novel pharmacophore features of flavonoids by using cell-free, cell-based and in silico docking studies. These results contribute to the development of new BACE-1 inhibitors for the treatment of AD. 相似文献
3.
Nicolas Charrier Brian Clarke Leanne Cutler Emmanuel Demont Colin Dingwall Rachel Dunsdon Julie Hawkins Colin Howes Julia Hubbard Ishrut Hussain Graham Maile Rosalie Matico Julie Mosley Alan Naylor Alistair O’Brien Sally Redshaw Paul Rowland Virginie Soleil Kathrine J. Smith Sharon Sweitzer Gareth Wayne 《Bioorganic & medicinal chemistry letters》2009,19(13):3664-3668
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer’s disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays. Amongst them, GSK188909 (compound 2) had favorable pharmacokinetics and was the first orally bioavailable inhibitor reported to demonstrate brain amyloid lowering in an animal model. In this Letter, we describe the reasons that led us to favor a second generation of inhibitors for further in vivo studies. 相似文献
4.
5.
Akhil Kumar Gaurava Srivastava Arvind S. Negi 《Journal of biomolecular structure & dynamics》2019,37(2):275-290
BACE-1 and GSK-3β both are potential therapeutic drug targets for Alzheimer’s disease. Recently, both these targets received attention for designing dual inhibitors. Till now only two scaffolds (triazinone and curcumin) derivatives have been reported as BACE-1 and GSK-3β dual inhibitors. In our previous work, we have reported first in class dual inhibitor for BACE-1 and GSK-3β. In this study, we have explored other naphthofuran derivatives for their potential to inhibit BACE-1 and GSK-3β through docking, molecular dynamics, binding energy (MM-PBSA). These computational methods were performed to estimate the binding affinity of naphthofuran derivatives towards the BACE-1 and GSK-3β. In the docking results, two derivatives (NS7 and NS9) showed better binding affinity as compared to previously reported inhibitors. Hydrogen bond occupancy of NS7 and NS9 generated from MD trajectories showed good interaction with the flap residues Gln73, Thr72 of BACE-1 and Arg141, Thr138 residues of GSK-3β. MM-PBSA and energy decomposition per residue revealed different components of binding energy and relative importance of amino acid involved in binding. The results showed that the binding of inhibitors was majorly governed by the hydrophobic interactions and suggesting that hydrophobic interactions might be the key to design dual inhibitors for BACE1-1 and GSK-3β. Distance between important pair of amino acid residues indicated that BACE-1 and GSK-3β adopt closed conformation and become inactive after ligand binding. The results suggested that naphthofuran derivatives might act as dual inhibitor against BACE-1 and GSK-3β. 相似文献
6.
Bäck M Nyhlén J Kvarnström I Appelgren S Borkakoti N Jansson K Lindberg J Nyström S Hallberg A Rosenquist S Samuelsson B 《Bioorganic & medicinal chemistry》2008,16(21):9471-9486
Several BACE-1 inhibitors with low nanomolar level activities, encompassing a statine-based core structure with phenyloxymethyl- and benzyloxymethyl residues in the P1 position, are presented. The novel P1 modification introduced to allow the facile exploration of the S1 binding pocket of BACE-1, delivered highly promising inhibitors. 相似文献
7.
Cole DC Stock JR Chopra R Cowling R Ellingboe JW Fan KY Harrison BL Hu Y Jacobsen S Jennings LD Jin G Lohse PA Malamas MS Manas ES Moore WJ O'Donnell MM Olland AM Robichaud AJ Svenson K Wu J Wagner E Bard J 《Bioorganic & medicinal chemistry letters》2008,18(3):1063-1066
Proteolytic cleavage of amyloid precursor protein by beta-secretase (BACE-1) and gamma-secretase leads to formation of beta-amyloid (A beta) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of A beta and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S(1) and S(2') pockets leading to submicromolar BACE-1 inhibitors. 相似文献
8.
Weijun Xu Gang Chen Weiliang Zhu Zhili Zuo 《Bioorganic & medicinal chemistry letters》2010,20(19):5763-5766
Nowadays identification of novel non-peptide β-secretase (BACE-1, hereinafter) inhibitors with low cytotoxicity and good blood–brain barrier (BBB) property holds common interest of drug discovery for Alzheimer’s disease. Twenty SPECS compounds were tested in BACE-1 FRET assays and methylthiazoletetrazolium (MTT) cytotoxicity experiment. Two compounds: 2 and 15 demonstrated IC50 values of 0.53 and 9.4 μM. In addition, 2 showed least toxic effect to the neuroblastoma cells. The results from both in silico and in vitro studies provided new pharmacophoric entities for chemical synthesis and optimization on the current discovered BACE-1 small molecule inhibitors. 相似文献
9.
Catherine Koukoulitsa Caroline Villalonga-Barber Robert Csonka Xanthippi Alexi Georgios Leonis Dimitris Dellis 《Journal of enzyme inhibition and medicinal chemistry》2016,31(1):67-77
It has been reported that beta amyloid induces production of radical oxygen species and oxidative stress in neuronal cells, which in turn upregulates β-secretase (BACE-1) expression and beta amyloid levels, thereby propagating oxidative stress and increasing neuronal injury. A series of resveratrol derivatives, known to be inhibitors of oxidative stress-induced neuronal cell death (oxytosis) were biologically evaluated against BACE-1 using homogeneous time-resolved fluorescence (TRF) assay. Correlation between oxytosis inhibitory and BACE-1 inhibitory activity of resveratrol derivatives was statistically significant, supporting the notion that BACE-1 may act as pivotal mediator of neuronal cell oxytosis. Four of the biologically evaluated resveratrol analogs demonstrated considerably higher activity than resveratrol in either assay. The discovery of some “hits” led us to initiate detailed docking studies associated with Molecular Dynamics in order to provide a plausible explanation for the experimental results and understand their molecular basis of action. 相似文献
10.
Nicolas Charrier Brian Clarke Emmanuel Demont Colin Dingwall Rachel Dunsdon Julie Hawkins Julia Hubbard Ishrut Hussain Graham Maile Rosalie Matico Julie Mosley Alan Naylor Alistair O’Brien Sally Redshaw Paul Rowland Virginie Soleil Kathrine J. Smith Sharon Sweitzer Pam Theobald David Vesey Gareth Wayne 《Bioorganic & medicinal chemistry letters》2009,19(13):3669-3673
Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer’s disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors. 相似文献
11.
Iserloh U Wu Y Cumming JN Pan J Wang LY Stamford AW Kennedy ME Kuvelkar R Chen X Parker EM Strickland C Voigt J 《Bioorganic & medicinal chemistry letters》2008,18(1):414-417
Based on lead compound 1 identified from the patent literature, we developed novel patentable BACE-1 inhibitors by introducing a cyclic amine scaffold. Extensive SAR studies on both pyrrolidines and piperidines ultimately led to inhibitor 2f, one of the most potent inhibitors synthesized to date. 相似文献
12.
Stephen Hanessian Zhihui Shao Claudia Betschart Jean-Michel Rondeau Ulf Neumann Marina Tintelnot-Blomley 《Bioorganic & medicinal chemistry letters》2010,20(6):1924-1927
Starting from peptidomimetic BACE-1 inhibitors, the P2 amino acid including the P2/P3 peptide bond was replaced by a rigid 3-aminomethyl cyclohexane carboxylic acid. Co-crystallization revealed an unexpected binding mode with the P3/P4 amide bond placed into the S3 pocket resulting in a new hydrogen bond interaction pattern. Further optimization based on this structure resulted in highly potent BACE-1 inhibitors with selectivity over BACE-2 and cathepsin D. 相似文献
13.
Jennings LD Cole DC Stock JR Sukhdeo MN Ellingboe JW Cowling R Jin G Manas ES Fan KY Malamas MS Harrison BL Jacobsen S Chopra R Lohse PA Moore WJ O'Donnell MM Hu Y Robichaud AJ Turner MJ Wagner E Bard J 《Bioorganic & medicinal chemistry letters》2008,18(2):767-771
The proteolytic enzyme beta-secretase (BACE-1) produces amyloid beta (Abeta) peptide, the primary constituent of neurofibrillary plaques, implicated in Alzheimer's disease, by cleavage of the amyloid precursor protein. A small molecule inhibitor of BACE-1, (diaminomethylene)-2,5-diphenyl-1H-pyrrole-1-acetamide (1, BACE-1 IC(50)=3.7 microM), was recently described, representing a new small molecule lead. Initial SAR investigation demonstrated the potential of accessing the nearby S(3) and S(1)(') substrate binding pockets of the BACE-1 enzyme by building substituents off one of the phenyl substituents and guanidinyl functional group. We report here the optimization of guanidinyl functional group substituents on 1, leading to potent submicromolar BACE-1 inhibitors. 相似文献
14.
Katharine Holloway M McGaughey GB Coburn CA Stachel SJ Jones KG Stanton EL Gregro AR Lai MT Crouthamel MC Pietrak BL Munshi SK 《Bioorganic & medicinal chemistry letters》2007,17(3):823-827
Several simple scoring methods were examined for 2 series of beta-secretase (BACE-1) inhibitors to identify a docking/scoring protocol which could be used to design BACE-1 inhibitors in a drug discovery program. Both the PLP1 score and MMFFs interaction energy (E(inter)) performed as well or better than more computationally intensive methods for a set of substrate-based inhibitors, while the latter performed well for both sets of inhibitors. 相似文献
15.
Novel non-peptide β-secretase inhibitors derived from structure-based virtual screening and bioassay
Weijun Xu Gang Chen Oi Wah Liew Zhili Zuo Hualiang Jiang Weiliang Zhu 《Bioorganic & medicinal chemistry letters》2009,19(12):3188-3192
This Letter describes an efficient approach by integrating virtual screening with bioassay technology for finding small organic inhibitors targeting β-secretase (BACE-1). Fifteen hits with inhibitory potencies ranging from 2.8 to 118 μM (IC50) against β-secretase were successfully identified. Compound 12 with IC50 of 2.8 μM is the most potent hit against BACE-1. Docking simulation from gold 3.0 suggests putative binding mode of 12 in BACE-1 and potential key pharmacophore groups for further designing of non-peptide compounds as more powerful inhibitors against BACE-1. 相似文献
16.
Stauffer SR Stanton MG Gregro AR Steinbeiser MA Shaffer JR Nantermet PG Barrow JC Rittle KE Collusi D Espeseth AS Lai MT Pietrak BL Holloway MK McGaughey GB Munshi SK Hochman JH Simon AJ Selnick HG Graham SL Vacca JP 《Bioorganic & medicinal chemistry letters》2007,17(6):1788-1792
A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-1 inhibitors containing an amine transition-state isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a trans-S,S-methyl cyclopropane P(3) which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux. 相似文献
17.
Shawn J. Stachel Craig A. Coburn Diane Rush Kristen L.G. Jones Hong Zhu Hemaka Rajapakse Samuel L. Graham Adam Simon M. Katharine Holloway Tim J. Allison Sanjeev K. Munshi Amy S. Espeseth Paul Zuck Dennis Colussi Abigail Wolfe Beth L. Pietrak Ming-Tain Lai Joseph P. Vacca 《Bioorganic & medicinal chemistry letters》2009,19(11):2977-2980
We have developed a novel series of heteroaromatic BACE-1 inhibitors. These inhibitors interact with the enzyme in a unique fashion that allows for potent binding in a non-traditional paradigm. In addition to the elucidation of their binding profile, we have discovered a pH dependent effect on the binding affinity as a result of the intrinsic pKa of these inhibitors and the pH of the BACE-1 enzyme binding assay. 相似文献
18.
Stefania Butini Emanuele Gabellieri Margherita Brindisi Alice Casagni Egeria Guarino Paul B. Huleatt Nicola Relitti Valeria La Pietra Luciana Marinelli Mariateresa Giustiniano Ettore Novellino Giuseppe Campiani Sandra Gemma 《Bioorganic & medicinal chemistry letters》2013,23(1):85-89
Aiming at identifying new scaffolds for BACE-1 inhibition devoid of the pharmacokinetic drawbacks of peptide-like structures, we investigated a series of novel peptidomimetics based on a 1,4-benzodiazepine (BDZ) core 1a–h and their seco-analogues 2a–d. We herein discuss synthesis, molecular modeling and in vitro studies which, starting from 1a, led to the seco-analogues (R)-2c and (S)-2d endowed with BACE-1 inhibition properties in the micromolar range both on the isolated enzyme and in cellular studies. These data can encourage to pursue these analogues as hits for the development of a new series of BACE-1 inhibitors active on whole-cells. 相似文献
19.
Pietrak BL Crouthamel MC Tugusheva K Lineberger JE Xu M DiMuzio JM Steele T Espeseth AS Stachel SJ Coburn CA Graham SL Vacca JP Shi XP Simon AJ Hazuda DJ Lai MT 《Analytical biochemistry》2005,342(1):144-151
The deposition of beta-amyloid peptides (A beta42 and A beta40) in neuritic plaques is one of the hallmarks of Alzheimer's disease (AD). A beta peptides are derived from sequential cleavage of amyloid precursor protein (APP) by beta- and gamma-secretases. BACE-1 has been shown to be the major beta-secretase and is a primary therapeutic target for AD. In this article, two novel assays for the characterization of BACE-1 inhibitors are reported. The first is a sensitive 96-well HPLC biochemical assay that uses a unique substrate containing an optimized peptide cleavage sequence, NFEV, spanning from the P2-P2' positions This substrate was processed by BACE-1 approximately 10 times more efficiently than was the widely used substrate containing the Swedish (NLDA) sequence. As a result, the concentration of the enzyme required for the assay can be as low as 100 pM, permitting the evaluation of inhibitors with subnanomolar potency. The assay has also been applied to related aspartyl proteases such as cathepsin D (Cat D) and BACE-2. The second assay is a homogeneous electrochemiluminescence assay for the evaluation of BACE-1 inhibition in cultured cells that assesses the level of secreted amyloid EV40_NF from HEK293T cells stably transfected with APP containing the novel NFEV sequence. To illustrate the use of these assays, the properties of a potent, cell-active BACE-1 inhibitor are described. 相似文献
20.
Fredrik Wångsell Francesco Russo Jonas Sävmarker Åsa Rosenquist Bertil Samuelsson Mats Larhed 《Bioorganic & medicinal chemistry letters》2009,19(16):4711-4714
Two series of drug-like BACE-1 inhibitors with a shielded tertiary hydroxyl as transition state isostere have been synthesized. The most potent inhibitor exhibited a BACE-1 IC50 value of 0.23 μM. 相似文献